Joslin Researcher Looking for Genes to Prevent Type 1 Diabetes

Monday, May 21, 2012

Stephan Kissler, Joslin’s new addition to the immunology team, is trying to crack the genetic code behind type 1 diabetes. And the end result could prevent the disease from happening in the first place.

Type 1 diabetes happens when the immune system starts destroying the cells that produce insulin. Researchers already know there is a genetic reason underlying the onset of diabetes. Now they’re trying to determine which genes are the actual culprits.

Developments in research techniques over the past five years have allowed scientists to map the genetic blueprint of individuals with and without genetics-based diseases (including type 1 diabetes) and compare the results—a process known as “genome-wide association studies”. This technique, when turned towards type 1 diabetes, reveals more than 50 different genes that are associated in one way or another with the disease.

Kissler’s new lab at Joslin will take those genes and test them, one by one, to see exactly how they function in type 1 diabetes.

“We know that they are associated with the disease, but we don’t know what in their function contributes to disease risk,” said Kissler. “The challenge is to pick these individual gene variations and to really drill down and try and understand their function both in the normal operation of the immune system and in the disease state.”

“So we study genes that are associated with type 1 diabetes by individually knocking them down using RNA interference,” he said.

RNA interference, something Kissler learned as a post-doc at MIT, is a process that uses strands of genetic material called RNA to inhibit the expressions of genes—meaning researchers can manually decide which genes get turned on or off and when by using RNA to block the pathways that lead to the genes’ switches.

RNA interference is popular in many types of biological research, including cancer and developmental studies. But those experiments are usually done in a dish under a microscope. Kissler and his research team are using a mouse model of type 1 diabetes to see what the genes do in a living animal.

In Kissler’s experiments, the mice are genetically prone to autoimmune diabetes that closely resembles type 1 diabetes in humans. The disease arises spontaneously, just as it would in a human. These mice are also primed for RNA interference from birth, so when the time comes—be it after the onset of the disease, or prior to—the team can turn off a specific gene to see how the loss of its function affects diabetes or the risk of diabetes.

“This is a nice way of mimicking a therapeutic intervention because if you were to treat a patient with a drug, you would obviously not give them a drug from birth. You would give it to them some time after diagnosis or some time before they’re diagnosed if they’re at very high risk,” said Kissler.

The inducement to shut down the gene is introduced through the mouse’s drinking water. And when the team stops spiking the water, the effects will eventually wear off and the gene will return to its normal function.

“And so it would be like a drug treatment where you give someone a drug for two weeks and then you stop giving them the drug,” said Kissler. “And we can do that with our mice, inhibit the gene for a certain time and then let it come back up.”

They are knocking down each gene for a determined period of time to see how the disease changes in the absence of those genes. Because it would not be feasible for a single laboratory to study each of the 50 or more genes implicated in type 1 diabetes with this approach, they decided to prioritize those genes that are also associated with other autoimmune diseases.

“The focus is on type 1 diabetes,” Kissler said, “but we are also going to cross over to other diseases because we might learn from these other models. At the same time we want to make sure our work has as wide a relevance as possible.”

Kissler thinks the collaborative atmosphere at Joslin will help move this research forward. “The environment at Joslin is probably the world’s best environment for the types of studies that I want to do,” he said.